METH0D FOR PREPARING THE CRYSTALLINE FORM I OF MELOXICAM
Field of the invention
The present invention relates to the crystalline
forms of meloxicam and to processes for their preparation
and interconversion. More specifically, it relates to the
new crystalline forms II, III and V of meloxicam; to the
processes for obtaining said new crystalline forms II,
III and V; and finally, to the processes for
interconverting the forms II, III, IV and V into the form
I.
Background of the invention
Meloxicam, 4-hydroxy-2-methyl-N-(5-methyl-2-
thiazolyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-
dioxide, is a known non-steroid anti-inflammatory drug
(NSAID). Standard NSAID"s inhibit both the isoform COX-1
ot cyclooxygenase, that is constitutively expressed in
many tissues, and the isoform COX-2, that is expressed as
a response to inflammatory mediators. Although current
NSAID"s present certain differences in potency as
inhibitors of these two enzymes, they generally inhibit
both. From a theoretical standpoint at least it would
therefore be advantageous to inhibit selectively COX-2
(reducing the inflammation) without affecting COX-1
(thereby leaving intact this enzyme, and thus reducing
possible kidney and gastric damage). The importance of
meloxicam in the pharmaceutical field is given by the
fact that this compound selectively inhibits COX-2 with
resnpect to COX-1 . Thus, meloxicam shows a selectivity
that is 75 times greater for COX-2 compared to COX-1, in
human recombinant enzymes. (Churchil L, Graham AC, Shih
C-K, et al. Selective inhibition of human cyclooxygenase-
2 by meloxicam. Inflammopharmacology, 1996; 4: 125-135).
It is known that meloxicam shows. polymorphism, with
two different crystalline forms known: the zwiterionic
form (hereinafter referred to as form IV) and the enolic
form, or form I. The crystalline form I is the one
suitable for preparing pharmaceutical products (P. Luger
et al. Eur. J. Pharm. Sci.., 1996, 175).
Enolic form, or form I, of meloxicam (Formula A):
Zwiterionic form, or form IV, of meloxicam (Formula
B) :
In the current state of the art, meloxicam is
obtained by reacting isopropyl 4-hydroxy-2-methyl-2H-l,2-
benzothiazine-3-carboxylate 1,1-dioxide (or other
derivatives of carboxylic acid) and 2-amino-5-
methylthiazol in xylene at reflux with partial
distillation. The meloxicam thus obtained must be
purified for adequate quality. Said purification is
performed by crystallisation in organic solvents such as
dichloroethane or 1,2-dichlorobenzene (see DE 2756113).
The paper by P. Luger et al. Eur. J. Pharm. Sci., 1996,.
175 describes the preparation of meloxicam, characterised
as form I, by recrystallisation in non-polar solvents.
This same document describes the preparation of the form
IV or zwiterionic form by treating meloxicam in an
aqueous medium with sodium hydroxide followed by acetic
acid.
The methods for obtaining the form I of meloxicam
have the disadvantage of relyinq on orqanic solvents.
This means that, in addition to the high cost of the
solvent, it must be later removed and/or recovered. In
addition, yields obtained by these crystallisation
methods are moderate or relatively lew (
These documents do not discuss the possibility of
interconverting the form IV into the form I, nor the
temperature and time used in the crystallisations. They
also do not describe the possibility of directly
obtaining the form I in an aqueous medium by treatment
with sodium hydroxide and acetic acid.
Thus, there is a need for a method for preparing the
form I of meloxicam that does not suffer from the
drawbacks of known methods, as well as new crystalline
forms that serve as intermediates or starting products
for preparing the form I of meloxicam and, finally, for
processes for preparing said crystalline forms.
Summary of the invention
Through exhaustive and laborious research the
inventors have developed a method by which,surprisingly,
the form I of meloxicam can be obtained with excellent
yields by cryscallisation of meloxicam in an aqueous
medium, a medium hitherto described for obtaining the
form IV. This implies an advantage over previous methods
as it avoids using organic solvents, which imply a need
of additional installations as well as harming the
environment. This method also provides a suitable process
for purification of meloxicam. Thus, an aspect of the
present invention is a method for obtaining and purifying
the form I of meloxicam from meloxicam.
A second aspect of the invention consists of new
crystalline forms of meloxicam, named forms II, III and
V, as well as the processes for preparation thereof.
these crystalline forms can serve as intermediates or
pure starting products for preparing the form I, or even
open paths for preparation of new pharmaceutical
formulations of meloxicam.
Finally, the inventors have developed processes
allowing to convert the crystalline forms II, III, IV and
V of meloxicam into the form I. This is thus the third
aspect of the invention. These processes allow
transforming the various crystalline forms of meloxicam
into the form I, which is the forrr. currently used in
pharmaceutical preparations of meloxicam.
The present specification has 14 figures. Figures 1,
2, 3, 4 and 5 show the infrared spectra of the
crystalline forms I, II, III, IV and V of meloxicam.
Figures 6, 7, 8, 9 and 10 show the X-ray diffractograms
of the crystalline forms I, II, III, IV and V of
meloxicam. Finally, figures 11, 12, 13, and 14 show the
Raman spectra of the crystalline forms I, II, III, IV and
V of meloxicam.
Detailed description of the invention
As mentioned above, the first aspect of the present
invention consists in a method for preparing meloxicam
form I, represented by the Formula A,
The first aspect of the invention consists in a
method for preparing the crystalline form I of meloxicam,
involving dissolving meloxicam in a mixture of water and
NaOH, and the subsequent addition of an acid for
precipitating the crystalline form I of meloxicam,
maintaining during the process a temperature between 65°C
and the reflux temperature.
Throughout the present application document the term
"meloxicam" refers to the crude product obtained in any
of the reactions for preparing said compound known in the
state of the art; for example, by reacting isopropyl 4-
hydroxy-2-methyl-2H-l,2-benzothiazine-3-carboxylate 1,1-
dioxide (or other derivatives of carboxylic acid) and 2-
amino-5-methylthiazol in xylene at reflux with partial
distillation.
The acid used in the reaction of the first aspect of
the invention can be an organic or inorganic acid,
preferably hydrochloric, acetic or methansulphonic acid,
and more preferably acetic acid. The acid is preferably
added until reaching a pH of 3 to 5.5. The temperature of
such process, with the exception of the crystallisation
step, is maintained between 65°C and the reflux
temperature, preferably between 65°C and 80°C, and more
preferably at 65°C, 80°C or 100°C. The amount of NaOH
added is preferably 1 to 1.5 equivalents of NaOH with
respect to meloxicam.
Within the first aspect of the invention is a
variation of the previous method, in which the meloxicam
is dissolved in a mixture of water, NaOH and an organic
solvent chosen from: an alcohol such as for example
ethanol, xylene, toluene and dimethylformamide (DMF), and
at a temperature that is maintained throughout the
process between 50°C and the reflux temperature.
The acid used, as in the previous process, is an
organic or inorganic acid, preferably hydrochloric,
acetic or methansulphonic acid, and more preferably
acetic acid. The acid is preferably added until reaching
a pH of 3 to 5.5. Preferred mixtures of solvents are:
water/xylene 12.5:1 (v/v), water/DMF (v/v) between 1:1
and 8:1 and, finally, water/ethanol (v/v) between 10:1
and 1:1. The process temperature, with the exception of
the precipitation step, is preferably between 50 and
80°C, more preferably 50°C, 63°C or 70°C. The amount of
NaOH added is preferably 1 to 1.5 equivalents of NaOH
with respect to meloxicam.
As mentioned above, the second aspect of the
invention are new, crystalline forms of meloxicam,
denominated forms II, III and V, as well as the processes
for preparing them.
The crystalline form II of meloxicam is
characterised by the following values of its infrared
spectrum (see figure 2):
IR (K3r): v 3104, 2974, 2927, 2880, 2858, 1620, 1603,
1549, 1523, 1455, 1417, 1403, 1349, 1303, 1289, 1270,
1240, 1221, 1182, 1156, 1127, 1119, 1066, 1042, 939, 856,
842, 807, 779, 762, 731, 693, 644, 609, 574, 565, 531,
504, 45 4 cm-1;
by the following values of its Raman spectrum (see
figures 11-14):
20 (vs), 31 (s), 73 (m) , 100 (s) , 371 (m) , 407 (s) , 506
(m) , 646 (m) , 668 (m) , 1121 (s), 1128 (sh) , 1155 (s) ,
1161 (s), 1267 (s), 1310 (vs), 1333 (vs), 1347 (vs), 1359
(vs), 1438 (s), 1476 (s), 1538 (vs), 1557 (vs) , 1595
(vs), 1611 (vs);
and by the X-ray diffractogram of figure 7.
The Method for preparing the crystalline form II of
meloxicam involves carrying out the following steps:
a) dissolving meloxicam in a mixture of water and NaOH
at 45-50°C, with a water / meloxicam (v(ml) / w(g))
ratio of 30 to 35,
b) adding an acid until obtaining a pH of 3-5.5,
maintaining the temperature of step a),
c) maintaining the suspension at the temperature of
step a) for 30 to 90 minutes, preferably 60
minutes, and
d) cooling and isolating the precipitate.
The mixture of water and NaOH used in step a) of the
method for preparing the crystalline form II of meloxicam
contains preferably 1 to 1.5 equivalents of NaOH with
respect to meloxicam. The acid added in step b) is
preferably acetic acid.
The crystalline form III of meloxicam is
characterised by the following values of its infrared
spectrum (see figure 3):
IR (KBr): v 3128, 2979, 2944, 2921, 1615, 1595, 1552,
1518, 1457, 1396, 1348, 1324, 1301, 1285, 1264, 1237,
1220, 1181, 1152, 1140, 1130, 1118, 1064, 1043, 992, 937,
860, 840, 807, 781, 758, 730, 688, 641, 607, 573, 565,
533, 523, 502, 454 cm"1;
by the following values of its Raman spectrum (see
figures 11-14):
27 (s), 37 (s), 48 (s) , 63 (s), 97 (m) , 407 (s) , 1119
(m) , 1159 (m) , 1261 (m) , 1309 (s), 1323 (vs) , 1357 (s),
1540 (vs), 1595 (vs);
and by the X-ray diffractogram of figure 8.
The method for preparing the crystalline form III of
meloxicam involves the following steps:
a) dissolving meloxicam in a mixture of water, NaOH
and xylene at 45-50°C, with the concentration of
meloxicam being from 15 to 20 ml of water/g of
meloxicam and with the concentration of xylene
being from 5 to 10% by weight with respect to
meloxicam,
b) adding an acid for 30 to 90 minutes until obtaining
a pH of 3-5.5, maintaining the temperature of step
a), and
c) cooling and isolating the precipitate.
The mixture of water, NaOH and xylene used in step
a) of the method for preparation of the form III of
meloxicam preferably includes 1 to 1.5 equivalents of
NaOH with respect to meloxicam. The acid added in step b)
is preferably acetic acid.
The crystalline form V of meloxicam is characterised
by the following values of its infrared spectrum (see
figure 5):
IR (KBr): v 3110, 2942, 2919, 2879, 2858, 1623, 1600,
1549, 1522, 1458, 1402, 1351, 1323, 1301, 1277, 1267,
1221, 1183, 1153, 1066, 1042, 985, 964, 939, 846, 804,
783, 763, 731, 697, 645, 609, 574, 566, 528, 503, 452 cm-
1.
by the values of its Raman spectrum (see figures 11-14):
16 (vs), 31 (sh), 47 (sh), 408 (m) , 1119 (m) , 1159 (m) ,
1261 (m), 1309 (s) , 1323 (vs), 1357 (s), 1540 (vs) , 1595
(vs) .
and by the X-ray diffractogram of figure 10.
The method for preparing the crystalline form V of
meloxicam involves carrying out the following steps:
a) dissolving meloxicam in a mixture of water, NaOH
at 40-45°C, with a ratio of water / meloxicam
(v(ml) / w(g)) under 30 ml,
b) adding an acid for 30 a 90 minutes until
obtaining a pH of 3-5.5 maintaining the
temperature of step a) ,
c) cooling and isolating the precipitate, and
d) drying the precipitate in a vacuum at a
temperature of 50 to 70°C, preferably 55 to 65
°C, for 1 to 24 hours, preferably 18 to 22 hours.
The mixture of water and NaOH used in the method for
preparation of the crystalline form V of meloxicam
contains preferably 1 to 1.5 equivalents of NaOH with
respect to meloxicam. The acid added in step b) is
preferably acetic acid.
As mentioned before, the third aspect of the
invention consists in methods for converting the
crystalline forms II, III, IV and V of meloxicam into the
form I of said compound.
The method for converting the crystalline form II of
meloxicam into the form I involves the following steps:
a) preparing a suspension of the form II of
meloxicam in water,
b) heating the suspension to a temperature between
50°C and reflux temperature, and stirring at this
temperature for 1 to 12 hours, and
c) cooling and isolating the precipitate.
Two methods have been developed for converting the
crystalline form III of meloxicam into the form I. The
first of these involves the following steps:
a) preparing a suspension of the form III of
meloxicam in water,
b) heating the suspension to a temperature between
65°C and reflux temperature, preferably 70°C, and
stirring at this temperature for 12 to 24 hours,
and
c) cooling and isolating the precipitate.
The second method for converting the crystalline form
III of meloxicam into the form I involves the following
steps:
a) preparing a suspension of the form III of
meloxicam in an alcohol, preferably methanol,
ethanol or isopropanol,
b) heating to reflux for 1 to 24 hours, preferably
from 4 to 12 hours, and
c) isolating the precipitate.
The method for converting the crystalline form IV of
meloxicam into the form I involves the steps:
a) preparing a suspension of the form IV of
meloxicam in water,
b) heating the suspension to a temperature between
5C°C and reflux temperature, and stirring at this
temperature for 1 to 24 hours, and
c) cooling and isolating the precipitate.
Finally, the method for converting the crystalline
form V of meloxicam into the form I involves the steps:
a) preparing a suspension of the form V of meloxicam
in water or in an organic solvent, with this
organic solvent preferably being an alcohol such
as for example isopropanol, toluene or
tetrahydrofuran.
b) heating the suspension to a temperature between
50°C and reflux temperature, and stirring at this
temperature for 1 to 12 hours, and
c) cooling and isolating the precipitate.
The following examples are provided only for
purposes of illustration of the present invention.
Example 1
Preparation of the form I at 65°C
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddies, a reflux cooling
system, thermometer and addition funnel, are loaded 4 50
ml of water, 2.04 g (1.2 eq) of NaOH flakes and 15 g of
meloxicam. The mixture is heated to 65°C using a
thermostated bath. Then are added during 1 hour 4.8 g of
80% acetic acid (1.5 eq) in 100 ml of treated water. When
addition has finished it is cooled to room
temperature. The precipitate is filtered and washed with
2 x 15 ml of water. 14.2 g of meloxicam are obtained
(yield: 96,8%). The isolated product corresponds to the
form I.
Example 2
Preparation of the form I at 80°C .
In a glass reactor of 500 ml volume,, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel of 10 ml volume-,
are leaded 250 ml of water, 2.04.g (1.2 eq) of NaOH
flakes and 15 g of meloxicam. The mixture is heated to
80°C using a thermostated bath until all of the product
has dissolved. Then are added during 1 hour 4.8 g of 80%
acetic acid (1.5 eq) . It is maintained for 45 min to 1
hour at: 80°C and then cooled to room temperature. It
is filtered and washed with 2 x 20 ml of water. 14,93 g
of meloxicam are obtained (yield: 99", 5%). The isolated
product corresponds to the form I.
Example 3
Preparation of the form I at 100°C
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 4 50
ml of water, 2.04 g (1.2 eq) of NaOH flakes and 15 g of
meloxicam. The mixture is heated to 100°C using a
thermostated bath. Then are added during 1 hour 4.8 g of
80% acetic acid (1.5 eq) . When addition has finished it
is cooled to room temperature. The precipitate is
filtered and washed with 2 x 15 ml of water. 14.44 g of
meloxicam are obtained (yield: 96.3%). The isolated
product corresponds to the form I.
Example 4
Preparation of the form I at 80°C with 35% hydrochloric
acid
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux, cooling
system, thermometer and addition funnel, are, loaded 450
ml of water, 2.04 -g (1.2 eq) of NaOH flakes and 15 g of
meloxicam. The mixture is heated to 80°C using a
thermostated bath. Then are added during 1 hour 5.34 g of
35% hydrochloric acid (1.2 eq). When addition has
finished (pH=5.5) the mixture is cooled to room
temperature. The precipitate is filtered and washed with
2 x 15 ml of water. 14.42 g of meloxicam are obtained
(yield: 96%) . The isolated product corresponds to the
form I.
Example 5
Preparation of the form I at 80°C with methansulphonic
acid
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 4 50
ml of water, 2.05 g (1.2 eq) of NaOH flakes and 15 g of
meloxicam. The mixture is heated to 80°C using a
thermostated bath. Then are added during 1 hour a
solution of 4.92 g of methansulphonic acid (1.2 eq) in 10
ml of water. When addition has finished (pH=5.0) the
mixture is cooled to room temperature. The precipitate
is filtered and washed with 2 x 15 ml of water. 14.32 g
of meloxicam are obtained (yield: 95%). The isolated
product corresponds to the form I.
Example 6
Preparation of the form I at 70°C in a 10:1 water/ethanol
mixture
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 250
ml of water, 2.04 g (1.2 eq) of NaOH flakes and 15 g of
neloxicam. The mixture is heated to 70°C using a
thermostated bath and 25 ml of ethanol are added. Then
are added for 1 hour 4.8 g of 80% acetic acid (1.5 eq).
When addition has finished it is cooled to room
temperature. The precipitate is filtered and washed with
2 x 15 ml of water. 14.24 g of meloxicam are obtained
(yield: 95%) . The isolated product corresponds to the
form I.
Example 7
Preparation of the form I at 50°C in a 1:1 ethanol/water
mixture
In a glass reactor of 700 ml volume, provided, with
mechanical stirring by Teflon paddies, a reflux cooling
system, thermometer and addition funnel, are loaded 200
ml of water, 2.04 g (1.2 eq) of NaOH flakes, 15 g of
meloxicam and 200 ml of ethanol. The mixture is heated to
50°C using a thermostated bath. Then are added during 1
hour 4.8 g of 80% acetic acid (1.5 eq). When addition has
finished it is cooled to 0/5°C. The precipitate is
filtered and washed with 2 x 15 ml of treated water.
14.16 g of meloxicam are obtained (yield: 94%). The
isolated product corresponds to the form I.
Example 8
Preparation of the form I at 63°C in a 1:1 DMF/water
mixture
In a glass reactor of 700 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 184
ml of water, 2.04 g (1.2 eq) of NaOH flakes, 15 g of
meloxicam and 184 ml of DMF. The mixture is heated to
63°C using a thermostated bath. Then are added during 1
hour 4.8 g of 80% acetic acid (1.5 eq). When addition has
finished the mixture is maintained at 63°C for 1 h and
then it is cooled to 0/5°C. The precipitate is filtered
and washed with 2 x 15 ml of water. 13.12 g of meloxicam
are obtained (yield: 87%). The isolated product
corresponds to the form I.
Example 9
Preparation of the form I at 50°C in a 8:1 water/DMF
mixture
In a glass reactor of 500 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 250
ml of water, 2.04 g (1.2 eq) of NaOH flakes, 15 g of
meloxicam and 30 ml of dimethylformamide (DMF). The
mixture is heated to 50°C using a thermostated bath. Then
are added during 1 hour 4.8 g of 80% acetic acid (1.5 eq)
in 50 ml of treated water. When addition has finished the
mixture is kept with stirring for 2h. It is cooled to
room temperature. The precipitate is filtered and
washed with 2 x 15 ml of water. 14.53 g of meloxicam are
obtained (yield: 97%). The isolated product corresponds
to the form I.
Example 10
Preparation of the crystalline form II
In a glass reactor of 10 1 volume provided with
mechanical stirring by stainless steel paddles and a
thermometer are loaded 9 liters of water and 41 g (1.2
eq) of NaOH flakes, then adding 300 g of meloxicam. The
mixture is heated to 50°C and 3 g are added of DAB-VI
carbon, and after 20 min it is filtered and washed with 1
1 of treated water. Maintaining the filtrate temperature
between 45-50°C a solution is adced of 192 g of 80%
acetic acid (3 eq) in 3 1 of water. When addition has
finished, the suspension is maintained for one hour at
4 5-50°C and afterwards it is cooled to room
temperature. If is filtered, washed with 3. litres of
water and dried. 288.6 g of meloxicam are obtained
(yield: 96%). The isolated product corresponds to the
crystalline form II.
Example 11
Preparation of the crystalline form III
In a glass reactor with 500 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel of 10 ml volume,
are loaded 250 ml of water, 2.04 g (1.2 eq) of NaOH
flakes, 15 g of meioxicam and 2 ml de xylene (ca. 10%
w/w). The suspension is heated to 50°C in a thermostated
bath until all the product has dissolved. Then are added
during 1 hour, 4.8 g (1.5 eq) of 80% acetic acid. When
addition has finished, the suspension is cooled to
room temperature, and the solid obtained is filtered
and washed with 2 x 20 ml of water. 14.71 g of meloxicam
are obtained (yield: 98%) . The isolated product
corresponds to the form :
Example 12
Preparation of the crystalline form V
In a glass reactor with 500 ml volume, provided with
mechanical stirring by Teflon paddles, a reflux cooling
system, thermometer and addition funnel, are loaded 300
ml of water, 1,35 g (1.2 eq) of NaOH flakes and 10 g of
meloxicam. The mixture is heated to 50°C using a
thermostated bath. Then are added during 1 hour 3,5 g of
80% acetic acid (1.5 eq) in 7 ml of water. When addition
has finished, it is cooled to room temperature. The
precipitate is filtered and washed with 70 ml of treated
water. The solid obtained is dried at 60°C in a vacuum.
After 21 h 9.43 g of meloxicam are obtained (yield: 94%).
The isolated product corresponds to the form V.
Example 13
Transformation of the form II into the form I by
digestion with water at 50°C.
In a glass reactor of 500 ml volume, provided with
mechanical stirring by stainless steel paddles, a a
reflux cooling system and a thermometer, are loaded 250
ml of water and 50 g of meloxicam form II. The suspension
is heated to 50°C. After 1.5 hours it is cooled, filtered
and washed with 50 ml of water. It is dried at 60°C .in a
vacuum providing 4 8.17 g (yield: 9 6%) of meloxicam form
Example 14
Transformation of the form III into the form I in water
In a balloon of 50 ml volume with magnetic stirring
and a reflux cooling system are loaded 5 g of meloxicam
form III and 25 ml of water. It is heated to 70°C and
maintained at this temperature overnight. Then it is
cooled to room temperature, filtered and dried at 60°C
in a vacuum to obtain 3.68 g (yield: 74%) of meloxicam
form I.
Example 15
Transformation of the form III into the form I by
digestion in methanol
In a balloon of 50 ml volume with magnetic stirring
and a reflux cooling system, are loaded 5 g of meloxicam
form III and 25 ml of methanol. It is heated to reflux
(dissolving partially) for approximately 1.5" h; it is
then cooled to room temperature, filtered and washed
with 5 ml of methanol. It is dried at 60°C in a vacuum to
obtain 4.65 g (yield: 93%) of meloxicam form I.
Example 16
Transformation of the form III into the form I by
digestion in IPA
In a balloon of 100 ml volume, with magnetic
stirring and a reflux cooling system, are loaded 5 g of
meloxicam form III and 50 ml of isopropanol. It is heated
to reflux and maintained at this temperature for 1 hour.
Then it is cooled, filtered and washed with 5 ml of IPA
It is dried at 60°C in a vacuum and 4.86 g are obtained
(vield: 97%) of meloxicam form I.
Example 17
Transformation of the crystalline form IV into the form I
In a balloon of 100 ml volume, with magnetic
stirring and a reflux cooling system, are loaded 5 g of
meloxicam form IV "and 50 ml of wazer, it is heated and
maintained 1/2 hour at 50°C and 1 hour at 60°C.
Afterwards it is cooled to room temperature and
filtered. The solid obtained is dried at 60°C in a vacuum
and 4.22 g are obtained (yield: 84%) of meloxicam form I.
Example 18
Transformation of the crystalline form V into the form I
in isopropanol
In a balloon of 5 0 ml volume, with magnetic
stirring and a reflux cooling system are loaded 5 g of
meloxicam form V and 25 mi of isopropanol. It is heated
at 50°C for approximately 1 h, then cooled to room
temperature, filtered and washed with 5 ml of
isoprcpanol. It is dried at 60°C in a vacuum and 4.53 g
are obtained (yield: 91%) of meloxicam form I.
Example 19
Transformation of the crystalline form V into the form I
in water
In a balloon of 50 ml volume, with magnetic stirring
and a reflux cooling system are loaded 5 g of meloxicam
form V and 25 ml of water. It is heated at 50°C for
approximately 2 h, then cooled to room temperature,
filtered and washed with 5 ml of water. It is dried at
60°C in a vacuum and 4.3 g are obtained (yield: 86%) of
meloxicam form I.
WE CLAIM :
1. Method for preparing the crystalline form I of
meloxicam,represented by the formula A
(A)
that involves dissolving meloxicam in a mixture consisting
of water and NaOH, and subsequent addition of an acid for
precipitation of the crystalline form I of meloxicam,
maintaining throughout the process a temperature between
65°C and the reflux temperature.
2. Method for preparing the crystalline form I of
meloxicam, represented by the formula A
(A)
wherein the meloxicam is dissolved in a mixture
consisting of water, NaOH and an organic solvent selected
from: an alcohol, xylene, toluene and dimethylformamide
(DMF), and wherein the temperature maintained throughout the
process is between 50°C to the reflux temperature.
3. Method for preparing the crystalline form I of
meloxicam as claimed in claim 1, comprised of the following
steps:
a) Dissolving meloxicam in a mixture consisting of water and
NaOH, at a temperature between 65°C and the reflux
temperature,
b) Adding an acid until obtaining a pH of 3 to 5.5; and
c) cooling and isolating the precipitate.
4. Method for preparing the crystalline form I of
meloxicam as claimed in claim 2, comprised of the following
steps:
a) Dissolving meloxicam in a mixture consisting of water,
NaOH and an organic solvent selected from: an alcohol,
xylene, toluene and dimethylformamide (DMF), at a
temperature between 50°C and the reflux temperature,
b) Adding an acid until obtaining a pH of 3 to 5.5; and
c) cooling and isolating the precipitate;.
5. Method for preparing the crystalline form I of
meloxicam as claimed in claims 1 and 3, wherein the process
temperature is between 65°C and 80°C.
6. Method for preparing the crystalline form I of
meloxicam as claimed in claims 2 and 4, wherein the process
temperature is between 50°C and 80°C.
7. Method for preparing the crystalline form I of
meloxicam as claimed in claims 2 and 4, wherein the organic
solvent used is xylene in a water/xylene ratio of 12.5:1
(v/v).
8. Method for preparing the crystalline form I of
meloxicam as claimed in claims 2 and 4, wherein the organic
solvent used is dimethyl formamide in a. water/DMF ratio of
1:1 to 8:1 (v/v).
9. Method for preparing the crystalline form I of
meloxicam as claimed in claims 2 and 4, wherein the alcohol
used is ethanol in a water/ethanol ratio of 1:1 to 10:1
(v/v).
10. Method for preparing the crystalline form I of
meloxicam as claimed in claims 1-9, wherein the acid added
is acetic acid.
11. Method for preparing the crystalline form II of
meloxicam that involves carrying out the following steps:
a) dissolving meloxicam in a mixture of water and NaOH at
45-50°C, with a water / meloxicam ratio (v(ml) / w(g)) of
30 to 35,
b) adding an acid until obtaining a pH of 3 to 5.5,
maintaining the temperature of step a),
c) maintaining the suspension at the temperature of step a)
for 30 to 90 minutes, and
d) cooling and isolating the precipitate.
12. Method for preparing the crystalline form II of
meloxicam as claimed in claim 11, wherein the acid added is
acetic acid.
13. Method for preparing the crystalline form III of
meloxicam that involves carrying out the following steps:
a) dissolving meloxicam in a mixture of water, NaOH and
xylene at 45-50°C, with the concentration of meloxicam
being 15 to 20 ml of water/g of meloxicam and the
concentration of xylene being 5 to 10% by weight with
respect to meloxicam,
b) adding an acid for 30 to 90 minutes until obtaining a pH
of 3 to 5.5, maintaining the temperature of step a), and
c) cooling and isolating the precipitate.
14. Method for preparing the crystalline form III of
meloxicam as claimed in claim 13, wherein the acid added is
acetic acid.
15. Method for preparing the crystalline form V of
meloxicam that involves carrying out the following steps:
a) dissolving meloxicam in a mixture of water, NaOH at 40-
45°C, with a water / meloxicam ratio (v(ml) / w(g)) under
30 ml,
b) adding an acid for 30 to 90 minutes until obtaining a pH
of 3 to 5.5, maintaining the temperature of step a),
c) cooling and isolating the precipitate, and
d) drying the precipitate in a vacuum at a temperature of 50
to 70°C for 1 to 24 hours.
16. Method for preparing the crystalline form V of
meloxicam as claimed in claim 15, wherein the acid added is
acetic acid.
17. Method for converting the crystalline form II of
meloxicam into the form I that involves carrying out the
following steps:
a) preparing a suspension of the form II of meloxicam in
water,
b) heating the suspension to a temperature between 50°C and
reflux temperature, and stirring at this temperature for
1 a 12 hours, and
c) cooling and isolating the precipitate.
18. Method for converting the crystalline form III of
meloxicam into the form I that involves carrying out the
following steps:
a) preparing a suspension of the form III of meloxicam in
water,
b) heating the suspension to a temperature between 65°C and
reflux temperature, and stirring at this temperature for
12 a 24 hours, and
c) cooling and isolating the precipitate.
19. Method for converting the crystalline form III of
meloxicam into the form I that involves carrying out the
following steps:
a) preparing a suspension of the form III of meloxicam in an
alcohol,
b) heating to reflux for 1 to 12 hours, and
c) cooling and isolating the precipitate.
20. Method for converting the crystalline form III of
meloxicam into the form I as claimed in claim 19 wherein the
alcohol used is methanol, ethanol or isopropanol.
21. Method for converting the crystalline form IV of
meloxicam into the form I that involves carrying out the
following steps:
a) preparing a suspension of the form IV of meloxicam in
water,
b) heating the suspension to a temperature between 50° and
reflux temperature, and stirring at this temperature for
1 to 24 hours, and
c) cooling and isolating the precipitate..
22. Method for converting the crystalline form V of
meloxicam into the form I that involves carrying out the
following steps:
a) preparing a suspension of the form V of meloxicam in
water or an organic solvent,
b) heating the suspension to a temperature between 50°C and
reflux temperature, and stirring at this temperature for
1 to 12 hours, and
c) isolating the precipitate.
23. Method for converting the crystalline form V of
meloxicam into the form I as claimed in claim 22 wherein the
organic solvent is isopropanol.
24. Method for converting the crystalline form V of
meloxicam into the form I as claimed in claim 22 wherein the
organic solvent is toluene.
25. Method for converting the crystalline form V of
meloxicam into the form I as claimed in claim 22 wherein the
organic solvent is tetrahydrofuran (THE").
The invention relates to the new crystalline forms
II, III and V of meloxicam; to the processes for
obtaining the crystalline forms I, II, III and V; and,
finally, to the interconversion processes of the forms
II, III, IV and V into the form I.